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Tim3 is a novel regulator of dendritic cell-T cell interactions in influenza

Tim3 是流感中树突状细胞-T 细胞相互作用的新型调节剂

基本信息

批准号：
9302650
负责人：
Josalyn L Cho
金额：
$ 20.09万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-15 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9302650
关键词：
Antigens Attenuated Autologous Biological Response Modifiers Blocking Antibodies Breeding Bronchoalveolar Lavage CD8-Positive T-Lymphocytes Cell Communication Cell physiology Cells Cellular Assay Cessation of life Critical Illness Cross Presentation Data Dendritic Cells Disease Effector Cell Foundations Future Generations Goals Host Defense Human Image Immune Immune response Immune system Immunoglobulins Immunology Infection Inflammation Influenza Injury Innate Immune Response Lead Lung Lung diseases MHC Class I Genes Measures Mediating Modeling Morbidity - disease rate Mucins Mus Natural Immunity Outcome Pathogenesis Patients Pharmaceutical Preparations Physicians Play Process Production Proteins Pulmonary Inflammation Respiratory Failure Role Sampling Scientist Secondary to Severity of illness T cell differentiation T-Lymphocyte Technology Therapeutic Training Viral Viral Antigens Viral Pathogenesis Viral Respiratory Tract Infection Virus Virus Diseases Virus Replication adaptive immune response antigen processing bronchial epithelium cell type cytokine genetic regulatory protein immunoregulation in vivo in vivo Model inflammatory lung disease killings langerin lung injury mortality mouse model novel novel strategies novel therapeutic intervention novel therapeutics prevent public health relevance respiratory response secondary infection targeted treatment trafficking uptake

项目摘要

DESCRIPTION (provided by applicant): Influenza is a major cause of morbidity and mortality, leading to thousands of deaths and many more episodes of respiratory failure annually. Current therapies target the virus and are therefore limited by the capacity of influenza to rapidly evolve and are frequently ineffective in critically ill patients. Clearly, new therapeutic strategies are needed. Respiratory failure in influenza often results from a dysregulated immune response to the virus. Prolonged viral replication or persistent inflammation resulting in immune-mediated lung injury can lead to severe pneumonitis and predisposes the host to secondary infections. Modulation of the host immune response has been proposed as a novel approach to therapy. Thus, a better understanding of host mechanisms that promote viral clearance and prevent immune-mediated lung injury may have powerful therapeutic implications. T cell immunoglobulin and mucin domain 3 (Tim3) is a regulatory protein expressed on innate immune cells, including dendritic cells (DCs), and terminally differentiated T cells. Current evidence suggests that Tim3 is important for both initiation of the innate immune response and termination of the adaptive immune response. We propose that modulation of Tim3 activity can be used to augment host defense and attenuate immune- mediated lung injury in influenza infection. Cross presentation of viral antigens by CD103+ respiratory DCs (rDCs) is critical for the generation of an anti-viral CD8+ T cell response during influenza. Deletion of these cells significantly delays viral clearance and increases disease severity. We present data showing that Tim3 is highly expressed on CD103+ rDCs and that it regulates the function of these cells. We hypothesize that Tim3 promotes the early innate response to influenza by augmenting antigen cross presentation by CD103+ rDCs. In this application, we will define the role of Tim3 on CD103+ rDCs during influenza and delineate the mechanisms by which Tim3 mediates its activity. To facilitate the study of Tim3 on CD103+ rDCs, we have generated a genetically modified mouse that allows cell-specific deletion of Tim3. Specifically we propose (1) To determine the role of Tim3 on CD103+ rDCs in initiating the CD8+ T cell response to influenza, (2) To determine the mechanism by which Tim3 regulates antigen cross presentation by DCs and (3) To define the role of Tim3 on DC subsets in the human lung.

描述（由申请人提供）：流感是发病率和死亡率的主要原因，每年导致数千人死亡和更多呼吸衰竭发作。目前的治疗方法针对的是病毒，因此受到流感快速进化能力的限制